Nanoparticles are used in a broad range of applications such as nano-electronic convergence technology, in vivo imaging technology, medical applications, etc. Specifically, super-paramagnetic iron oxide nanoparticles are widely used in a variety of biomedical applications including, for example, a magnetic resonance imaging (‘MRI’) contrast agent, cell therapy, hyperthermia, drug delivery, cell separation, nucleic acid preparation, or the like.
The most important requirement for application in biomedical applications is primarily to ensure high quality nanoparticles and, in addition, to allow nanoparticles to have excellent dispersibility and stability in an aqueous medium. Here, the high quality nanoparticle may mean nanoparticles with features of; (i) uniformity of particle size, (ii) easy control of particle size, (iii) particle crystallinity, (iv) possibility in controlling particle morphology, etc. However, nanoparticles commercially available in the art are mostly synthesized in an aqueous system or may be obtained by synthesis in a gas phase. Nanoparticles generated by the foregoing processes have difficulty in preparing particles with a uniform shape and generally show low crystallinity. Further, it is difficult to manufacture nanoparticles having a uniform size and control the size of a particle.
Recently, numerous studies have been executed to develop a novel method for manufacturing metal oxide nanoparticles in an organic system, which have relatively high quality, that is, uniform size and favorable crystallinity, compared to nanoparticles synthesized in an aqueous system according to the related art.
As such, in the case where nanoparticles are synthesized in an organic solvent, uniformity and size control of the nanoparticles may sometimes be achieved by stabilization thereof using an organic additive during a synthesizing process. In this regard, since the surface condition of nanoparticles is influenced by a hydrophobic organic additive, the metal oxide nanoparticles may be easily dispersed in a hydrophobic organic solvent. However, when they are mixed with water, they do not have sufficient stability.
For such nanoparticles prepared in an organic solvent, hydrophobic properties of the surface of the nanoparticles may obscure stable dispersion of the nanoparticles in water, thus causing a problem for use in biomedical applications. Therefore, in order to use the nanoparticles in the foregoing applications, there is a need to develop a biocompatible dispersion stabilizer that reforms (or modifies) the surface of the nanoparticles in order to have hydrophilic properties and ensures a suitable condition so as to be homogeneously dispersed in an aqueous medium. In addition, development of a nanoparticle colloidal solution that is prepared using the biocompatible dispersion stabilizer described above, wherein the dispersion state is stably maintained in an aqueous system, is also required.
Among methods for dispersing nanoparticles in an aqueous system according to the techniques in the related art, use of a thin silica layer has currently been disclosed in the Journal of American Chemical Society, 2005, 127, 4990. According to the foregoing article, polyoxyethylene nonylphenylether is introduced to a cyclohexane solution and mixed with the same to form micro-micelle emulsion drops. Next, a sol-gel reaction of tetraethyl ortho-silicate (TEOS) is induced and nanoparticles are coated with a silica layer and dispersed in water. The above document described a process of coating the outer side of the nanoparticles with a hydrophilic silica layer to disperse the nanoparticles in water, wherein the nanoparticles were prepared in an organic solvent. In this case, the silica coating method using micro-emulsion entails a problem in that, since an amount of nanoparticles to be coated at just one time is very small, an amount of nanoparticle dispersion in an aqueous system manufactured in a single process is also greatly reduced. Moreover, according to the amount of nanoparticle colloids manufactured in the single process or an amount of polyoxyethylene nonylphenylether, the conditions of the micro-emulsion are altered. Therefore, there are difficulties in finely regulating a desired thickness of a silica layer, and attaining uniformity of the coated particles since the number of nanoparticles contained in the silica layer is altered. In the case where nanoparticles are stabilized by a silica layer, the foregoing techniques in the related art entail problems in that silane functional groups on the surface of the silica are not sufficiently stable but react to one another, therefore, the nanoparticles coated with the silica and dispersed in water were combined and became agglomerated over time. As a result, it was difficult to ensure storage stability of the dispersion over a long period of time.
In recent years, a method for dispersing nanoparticles in water using a polymer composed of phosphine oxide and polyethyleneglycol has been disclosed in the Journal of America Chemical Society (2005, 127, 4556). More particularly, the foregoing article described a nanoparticle dispersing method wherein, after reacting polyethyleneglycol with 1,2-bis(dichlorophosphino)ethane to synthesize a polymer having polyethyleneglycols bonded together, the polymer is subjected to a ligand exchange reaction with nanoparticles dispersed in a hydrophobic solvent, thereby enabling dispersion stabilization of the nanoparticles and uniformly dispersing the same in water. The disclosed method uses a simple preparation method and utilizes ligand exchange to disperse nanoparticles in water. However, since phosphorus atom (P) is likely to oxidize and become a phosphoryl group, a coating polymer must be synthesized in an inert atmosphere using nitrogen or argon. Further, since the polymer is in a cross-linked state, a problem in introducing a functional group to bond functional ligands in vivo such as DNA, RNA, a monoclonal antibody or other functional proteins, still remains.
Scientists have recently conducted a number of studies upon mussels as a potential origin of bio-adhesives. Mussels generate and secrete a sticky material which is functionally differentiated to allow the mussels to be stationary or anchor in the water, in a marine environment having characteristics of salinity, humidity, tidal flow, turbulent flow, waves, etc. The mussel strongly adheres to the surface of a material in water, using threads composed of a fiber bundle secreted from legs thereof. At the end of each fiber, a plaque comprising a water-proof adhesive is present to allow the mussel to adhere to a wet solid surface. Such thread protein contains a large quantity of 3,4-dihydroxyphynyl-L-alanine (DOPA), which is an amino acid obtained by hydroxylation of tyrosine groups using a polyphenol oxidase. 3,4-dihydroxyphenyl (catechol) on a side branch of DOPA may create a very strong hydrogen bond with the hydrophilic surface and/or be strongly bonded with metal ions, metal oxides (Fe3+, Mn3+), semi-metal (silicon), or the like.
Occurrence of a metastatic cancer decisively influences prognosis and treatment of a cancer. The occurrence of a metastatic cancer may be determined by presence or absence of lymph node metastasis and occurrence of a metastatic lymph node cancer is currently diagnosed by surgically biopsying the lymph node. However, this is an invasive method involving significant difficulties to both a patient and a physician. On the other hand, non-invasive techniques such as use of CT, MRI, PET, etc. may be employed to detect occurrence of a metastatic cancer, but, incurs a problem in that cancer may generally be detected when its size is 5 mm or more. Accordingly, there is still a need for a method capable of non-invasively diagnosing metastatic cancer having a relatively small size.
A method for detecting metastatic cancer by injecting iron oxide nanoparticles in vivo and using an magnetic resonance image to show iron oxide deposition on lymph nodes has been introduced (Mukesh G. Harisinghani, M.D., Jelle Barentsz, M.D., Ph.D., Peter F. Hahn, M.D., Ph.D., Willem M. Deserno, M.D., Shahin Tabatabaei, M.D., Christine Hulsbergen van de Kaa, M.D., Ph.D., Jean de la Rosette, M.D., Ph.D., and Ralph Weissleder, M.D., Ph.D., and New England Journal of Medicine 2003; 348:2491-2499). According to the disclosed method, after stabilizing iron oxide nanoparticles in an aqueous system using a hydrophilic material, the treated nanoparticles are introduced in vivo and, after a predetermined time, lymph node tissues with cancer as well as normal lymph node tissues are observed through an MRI. Based on a difference in observed results therebetween, the occurrence of cancer may be diagnosed. Using the foregoing method, AMAG Co. (United States) has developed a MRI contrast agent named ‘COMBIDEX’ for contrast enhanced lymphography. However, the above contrast agent often causes adverse effects after in vivo administration and/or has poor selectivity, thus, is not widely used. Accordingly, there is still a need for developing an improved iron oxide-based contrast agent for contrast enhanced lymphography, having excellent selectivity and reduced adverse effects.